Drug Interactions between Opioids and Antiretroviral Medications: Interaction between Methadone, LAAM, and Delavirdine

Abstract

Understanding the drug interactions between antiretrovirals and opioid therapies may decrease toxicities and enhance adherence with improved HIV outcomes in opioid-dependent individuals. The authors report the results of a clinical pharmacology study designed to determine whether significant pharmacokinetic and/or pharmacodynamic interactions occur between the non-nucleoside reverse transcriptase inhibitor, delavirdine (DLV), and either methadone or levo-alpha acetyl methadol (LAAM) (n = 40). DLV significantly decreased methadone clearance (p = .018) and increased the methadone elimination half-life (p < .001) with a resultant increase in AUC of 19% and C(min)of 29%. The combined effect of DLV on the total concentration of LAAM and its active metabolites, norLAAM and dinorLAAM, was to significantly increase AUC by 43% (p < .001), C(max) by 30% (p = .013), and C(min) by 59% (p = .004) while decreasing T(max) (p = .05). Cognitive deficits over the seven-day study period as measured by the Mini-Mental State Examination, opioid withdrawal symptoms as measured by the Objective Opioid Withdrawal Scale, or complaints of adverse symptoms were not observed. Methadone and LAAM did not affect DLV concentrations. The findings from this study show that DLV treatment in methadone- or LAAM-maintained individuals results in altered opioid pharmacokinetics with an increased exposure and potential risk for opioid toxicity with methadone or LAAM treatment and an increased risk of cardiac toxicity with concomitant LAAM and DLV administration.

Interactions between Buprenorphine and Antiretrovirals. I. The Nonnucleoside Reverse-Transcriptase Inhibitors Efavirenz and Delavirdine

“…The general design of this study has been reported elsewhere [9,10]. Thirty-five individuals participated, including 10 opioid-dependent individuals who had been stable for at least 2 weeks while receiving a daily dose of sublingual buprenorphine/ naloxone of between 16/4 and 20/5 mg and who participated in a 24-h blood and urine sampling study to determine buprenorphine pharmacokinetics followed by administration of either EFV (600 mg daily) for 15 days or DLV (600 mg twice daily) for 7 days, as well as a second 24-h pharmacokinetic study in which blood and urine sampling for buprenorphine and antiretroviral plasma concentrations was performed.…”

“…This class of antiretrovirals has previously been shown to have important pharmacokinetic interactions with methadone. Among these, efavirenz (EFV), the most frequently prescribed medication in the class, is a potent inducer of CYP3A4 that has been shown to precipitate opiate withdrawal when administered with methadone [1], whereas delavirdine (DLV) is a known inhibitor of CYP3A4 that increases concentrations of methadone [9]. The goals of the present study included the following: (1) to determine whether the pharmacokinetics of the opioid dependence medication buprenorphine (administered in this study as the buprenorphine/naloxone combination tablet that is used in the clinical setting for the treatment of opioid dependence) are affected by coadministration of either of the NNRTI medications EFV or DLV; (2) to determine whether the pharmacokinetics of these NNRTIs are affected by coadministration of buprenorphine; and (3) to determine whether clinically significant pharmacodynamic effects or toxicities occur when buprenorphine is administered simultaneously with either NNRTI.…”

A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice

“…Methadone has a long half-life and it is unclear if prolonged co-administration of delavirdine and methadone would result in larger increases in AUC and the development of clinical symptoms; therefore, the co-administration of these medications should be undertaken judiciously and with close oversight [149]. A separate study demonstrated that methadone does not significantly effect delavirdine’s pharmacokinetics [150].…”

Management of opioid use disorders: a national clinical practice guideline

“…[43][44][45] Regarding adverse events, only a minor effect on corrected QT (QTc) interval duration has been reported with therapeutic doses of buprenorphine-naloxone, without proarrhythmic effects. 46,47 Conversely, methadone can increase the risk of a rare but fatal ventricular arrhythmia (torsades de pointes) because of its substantial QT-prolonging effects, especially at higher doses.…”